Description of Research
The secreted protein, Sonic hedgehog (Shh), plays an integral role in forming the ventral midline of the vertebrate central nervous system (CNS). In the absence of Shh function, ventral midline development is perturbed resulting in holoprosencephaly (HPE), a structural malformation of the brain, as well as neuronal patterning and path finding defects. Central to the understanding of ventral neural tube development is how Shh transcription is regulated in the CNS. Research in my laboratory employs genetic, genomic and biochemical approaches to uncover the cis and trans acting determinants of Shh expression in the mouse CNS. An understanding of how Shh expression is initiated in the ventral forebrain may provide insight into additional causes of holoprosencephaly.

Figure 1: Shh expression in the CNS is controlled by short and long range acting enhancers.

A second focus of research in my laboratory addresses the genetic programs underlying inner ear morphogenesis. The principal components for hearing (cochlea) and balance (vestibulum) are formed from ventral and dorsal outgrowths, respectively, of a common bilateral structure, the otocyst. Organization of the inner ear into auditory and vestibular components is established early in development and is heavily influenced by surrounding tissues. The proximity of the otocyst to the hindbrain suggested that extracellular signals that pattern the CNS might also polarize the otic epithelium along its dorsoventral axis. Experiments in my laboratory address the specific contributions of Shh and Wnt signaling pathways in promoting cochlear and vestibular development, respectively.

Figure 2: Morphology of the developing inner ear. Hearing and balance are coordinated by stimulation of vestibular (red) and auditory (green, yellow) hair cells in the semicircular canals and cochlea, respectively.

Rotation Projects
1. Screen for novel regulators of Shh transcription in the mouse central nervous system
2. Trace the lineage of Shh responsive cells in the hypothalamus
3. Identify and characterize novel genes regulated by Shh and Wnt signaling in the inner ear